2-(quinolonyl)-fused heterocycles as androgen receptor modulators

Abstract

The present invention is directed to novel 2-(quinolonyl)-fused heterocyclyl derivatives of the general formula (I) wherein R 1 , R 2 , R 3 , R 3a , R 4 , R 5 , R 6 and R 7 are as herein defined, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by the androgen receptor.

1. A compound of the formula (1a) 
                 
 
       wherein
 R 1  is hydrogen;  
 R 2  is hydrogen;  
 R 3  is halogenated lower alkyl;  
 R 3a  is absent or hydroxy;  
  represents an optional double bond; such that when R 3a  is absent, the double bond extends from the carbon atom of the ring bound to R 2  to the carbon atom of the ring bound to R 3 ;  
 R 4  and R 5  are taken together with the carbon atoms to which they are bound to form a six membered, heterocyclyl group containing two heteroatoms selected from the group consisting of O, N and S; wherein the heterocyclyl group is optionally substituted with one to four substituents independently selected from halogen or oxo; provided that when the substituent is oxo, then the substituent is bound to a S atom of the heterocyclyl group;  
 R 6  is hydrogen;  
 R 7  is selected from the group consisting of hydrogen and lower alkyl;  
 or a pharmaceutically acceptable salt, esteror prodrug thereof.  
 
     
     
       2. A compound as in  claim 1  wherein
 R 1  is hydrogen;  
 R 2  is hydrogen;  
 R 3  is trifluoromethyl;  
 R 3a  is absent or is OH;  
  represents an optional double bond; such that when R 3a  is absent, the double bond extends from the carbon atom of the ring bound to R 2  to the carbon atom of the ring bound to R 3 ;  
 R 4  and R 5  are taken together with the atoms to which they are bound to a heterocyclyl group selected from [1,4]-dioxanyl, 2,2,3,3,-tetrafluoro-[1,4]-dioxanyl, thiomorpholinyl, thiomorpholinyl-1,1-dioxide, thiomorpholinyl-1-oxide and morpholinyl;  
 R 6  is hydrogen;  
 R 7  is selected from the group consisting of hydrogen and methyl;  
 or a pharmaceutically acceptable salt, ester or prodrug thereof.  
 
     
     
       3. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 1 . 
     
     
       4. A method of treating a disorder mediated by an androgen receptor, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of  claim 1 , wherein the disorder is selected from the group consisting of prostate carcinoma, anorexia nervosa, breast cancer, AIDS, cahexia, male contraception and male performance. 
     
     
       5. A method of treating a condition selected from the group consisting of prostate carcinoma, anorexia nervosa, breast cancer, AIDS, cachexia, male contraception, and male performance, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of  claim 1 .